Ultrahypofractionated Radiotherapy versus Conventional to Moderate Hypofractionated Radiotherapy for Clinically Localized Prostate Cancer

Simple Summary Recently, shortening treatment time is becoming more important. Ultrahypofractionated radiotherapy (UHF) for localized prostate cancer is a fascinating treatment strategy; however, the concept of a well-balanced, optimal dose during UHF radiotherapy remains a contentious strategy, with only a few studies on UHF already reported. We must wait for the results of randomized trials several years away. Therefore, we tried to reveal the acceptable schedule in comparison to conventional to moderate hypofractionated radiotherapy so far. We found that UHF using EQD2 ≤ 100 Gy1.5 is a feasible UHF schedule with a good balance between toxicity and efficacy. Abstract The purpose of this study was to compare the toxicity (first endpoint) and efficacy (second endpoint) of ultrahypofractionated radiotherapy (UHF) and dose-escalated conventional to moderate hypofractionated radiotherapy (DeRT) for clinically localized prostate cancer. We compared 253 patients treated with UHF and 499 patients treated with DeRT using multi-institutional retrospective data. To analyze toxicity, we divided UHF into High-dose UHF (H-UHF; equivalent doses of 2 Gy per fraction: EQD2 > 100 Gy1.5) and low-dose UHF (L-UHF; EQD2 ≤ 100 Gy1.5). In toxicity, H-UHF elevated for 3 years accumulated late gastrointestinal and genitourinary toxicity grade ≥ 2 (11.1% and 9.3%) more than L-UHF (3% and 1.2%) and DeRT (3.1% and 4.8%, p = 0.00126 and p = 0.00549). With median follow-up periods of 32.0 and 61.7 months, the actuarial 3-year biochemical failure-free survival rates were 100% (100% and 100% in the L-UHF and H-UHF) and 96.3% in the low-risk group, 96.5% (97.1% and 95.6%) and 94.9% in the intermediate-risk group, and 93.7% (100% and 94.6%) and 91.7% in the high-risk group in the UHF and DeRT groups, respectively. UHF showed equivocal efficacy, although not conclusive but suggestive due to a short follow-up period of UHF. L-UHF using EQD2 ≤ 100 Gy1.5 is a feasible UHF schedule with a good balance between toxicity and efficacy.


Introduction
Prostate cancer became a major malignancy in developed countries [1]. As many curative treatment options exist, surgery, external beam radiotherapy, and brachytherapy, it is difficult to choose the best treatment option [2]. Recent advancements in radiotherapy for localized prostate cancer have enabled us to shorten the treatment period using hypofractionations and provide cost effectiveness and patient convenience. In the place of conventional 1.8-2-Gy fractionation, 2.3-3.4-Gy moderate hypofractionation has already become the standard of care [3]. Furthermore, ultrahypofractionation radiotherapy (UHF) of 5 Gy or more has emerged. The biological features of prostate cancer with a low α/β ratio also encouraged the adoption of these hypofractionations and UHF worldwide [2,3]. However, the concept of a well-balanced, optimal dose during UHF radiotherapy remains contentious, with only a few studies on the comparison of different UHF schedules already reported.
Ishiyama et al. reported an early experience of the safety and effectiveness of UHF in Japan using multi-institution data accumulation and created an open database for exploration [4][5][6]. We aimed to compare the outcomes of UHF with those of conventional to moderate hypofractionated radiotherapy. The superiority of high prescribed doses was confirmed with many randomized, controlled trials for localized prostate cancer [7] using biochemical failure-free survival (BFFS) rates. Then, the National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology (2019) state that doses of 70 Gy or less in conventional fractions are not enough of a dose to treat intermediate-or high-risk prostate cancer [2]. Therefore, we set a control group that used dose-escalated radiotherapy (DeRT) with a prescribed dose of 72 Gy or more, which is equivalent to doses of 2 Gy per fraction (EQD2) (74 Gy for intermediate-to high-risk groups). To reduce bias, we used the propensity score analysis, including an inverse probability of treatment weighting (IPTW) method and propensity score-matched pair analysis. The aim of the present study was to compare the efficacy and especially toxicity of UHF and DeRT.

Patients
We retrospectively examined 253 patients treated with UHF (open data for public use) [6] and 499 patients treated with dose-escalated radiotherapy (DeRT) [270 Uji-Takeda Hospital (tomotherapy) and 229 open data]. The patient eligibility criteria were (1) patients treated with UHF or DeRT, (2) the clinical stage T1-T4 and N0M0 with histology-proven adenocarcinoma; the availability and accessibility of pretreatment data (initial prostatespecific antigen = iPSA) level, T classification, and the Gleason score sum (GS) to determine the stage according to the NCCN 2015 risk classification as follows: low (T1-T2a, GS 2-6, and iPSA < 10 ng/mL), intermediate (T2b-T2c, GS 7, or PSA 10-20 ng/mL), and high (T3-T4, GS 8-10, or PSA > 20 ng/mL) [1]. Exclusion criteria were (1) metastasis cases, (2) node-positive cases, and (3) EQD2Gy < 72 Gy (<74 Gy for intermediate-or high-risk categories) ( Table 1). The purpose of this study was to compare the toxicity (first endpoint) and efficacy (second endpoint) of UHF and DeRT for clinically localized prostate cancer. The definition of biochemical failure-free survival rate (BFFS) was the time from the initiation of radiotherapy to the date of biochemical failure and/or last follow-up, whichever came first, according to the Phoenix definition (nadir, +2 ng/mL) [2].
The toxicity analysis was performed with Common Terminology Criteria for Adverse Events version 4.0. The patients undergoing UHF (open data) and a part of those undergoing DeRT (open data) provided informed consent during the process of building public data, and all patients treated at Uji-Takeda hospital provided written, informed consent. We performed this study in accordance with the Declaration of Helsinki. We obtained the permission of the Institutional Review Board (Kyoto Prefectural University of Medicine: ERB-C-1403).
In Uji-Takeda hospital, we used a 2.2 Gy/fraction schedule using D95 (95% of planning target volume (PTV) received at least the prescribed dose) of 74.8 Gy in 34 fractions (2.2 Gy/fraction) for intermediate-and high-risk patient, and 72.6 Gy in 33 fractions was used for low-risk cases, initially [8]. We changed the prescribed dose to 74 Gy (D95) in 37 fractions for the high-and intermediate-risk groups and 72 Gy in 36 fractions for the low-risk group (2 Gy/fraction). Between June 2007 and June 2009, we used a 2.2-Gy fraction schedule, which was changed to a modified 2-Gy fraction schedule from June 2009 to September 2013 [8].  [4]. Therefore, we examined the impact of this threshold not only on toxicity but also on the efficacy of UHF and DeRT, dividing UHF into two subgroups: H-UHF and L-UHF groups, using a cut-off value of EQD2 = 100 Gy 1.5 .

Statistical Analysis
We used The R stat package [10] for the statistical analyses. Student t-tests were used for normally distributed data. Mann-Whitney U-tests for skewed data were used to compare means or medians, and percentages were analyzed using chi-square tests. The biochemical control rate, survival, and accumulated toxicity were analyzed using the Kaplan-Meier method, and comparisons were made using log-rank tests. We used Cox's proportional hazards model for univariate and multivariate analyses of biochemical control rate. Statistical significance was set at p < 0.05. As we did not randomize the included patients, unbalanced baseline characteristics existed and could have led to a selection bias. Therefore, it influenced the decision to undergo UHF or DeRT. We used propensity score, which is defined here as the probability of being assigned to the DeRT or UHF group, given the patient characteristics. The logistic regression model was used in the calculation of the propensity scores, considering the baseline covariates shown in Table 2 (age, hormonal therapy history, T classification, GS, and pretreatment PSA). After the initial analysis of the whole cohort, we performed a propensity score-matched pair analysis to minimize the bias related to the choosing of and allocation to the DeRT or UHF groups. Five factors prescribed before were used to create a 1:1 matched cohort assigned to the UHF and DeRT groups.

Patient and Tumor Characteristics
We examined 752 patients with stage T1-T4 N0M0 prostate cancer treated using UHF or DeRT. Table 1 presents the baseline patient characteristics of the UHF and DeRT groups. The median follow-up duration for the entire cohort was 47 months (range, 9-97 months) and the median patient age was 72 years (range, 51-86 years). The UHF group was used to treat patients with the earlier disease and less hormonal therapy history with shorter follow-up periods than those in the DeRT group. After matching, there were no significant differences for all variables used for matching (Supplemental Table S1).

Late Toxicity
The incidence of late gastrointestinal (GI) and genitourinary (GU) toxicities is shown in Table 3. The higher incidence of GU toxicities and equivalent incidence of GI toxicities occurred in the UHF group in comparison with the DeRT group. Among subgroups, the H-UHF group showed an elevated incidence of GI and GU toxicities compared to the DeRT and L-UHF groups. Table 3. Late toxicity.

Toxicities
Grade

Biochemical Control, Overall, and Prostate Cancer-Specific Survival
The number of patients with biochemical failure was 45 in the DeRT group (9.01%) and 10 in the UHF group
No prostate cancer-related deaths were observed in this cohort. The 5-year prostate cancer-specific survival rates were 100% in both the UHF and DeRT groups.
No prostate cancer-related deaths were observed in this cohort. The 5-year prostate cancer-specific survival rates were 100% in both the UHF and DeRT groups.
The American Society for Radiation Oncology, American Society of Clinical Oncology, and American Urological Association guidelines recommend prescription doses be-
We thought that there is room for dose escalation for high-risk groups because of the assumption of a low α/ß ratio of 1.5 Gy for prostate cancer. We hope to improve tumor control while maintaining low levels of late toxicity using a large-fraction dose [16][17][18]. Unfortunately, current UHF clinical trials only support non-inferiority rather than superiority over conventional fractionation [11]. Royce et al. estimated the improvement of tumor control probability up to 95% using high EQD2 of 102 Gy (38.7 Gy in five fractions) compared with 90% when EQD2 of 97 Gy (37.6 Gy in five fractions) was used [20]. Although the biochemical control rate did not improve as per the literature and our findings [2,3,22], Zelefsky et al. reported positive biopsy rates of 47.6%, 19.2%, 16.7%, and 7.7% after 32.5 Gy, 35 Gy, 37.5 Gy, and 40 Gy in five fractions, respectively, which suggested the importance of dose escalation [24]. In addition, although late toxicity was higher than with L-UHF and DeRT, the frequency of toxicity grade ≥3 in the H-UHF group was only 2% in GI and 1% in GU (8% and 10% grade 2), which could be comparable to other studies [12,16,20,21]. Many trials showed similar or higher GI [15,16] and GU toxicity [12,21,25,26]. For instance, Zimmerman et al. reported grade 3-4 toxicity 12.5% in GI and 3.8% in GU (17.5% and 27.5% grade 2) in a phase II trial [26], and Kishan et al. reported 0.4% GI and 1.8% GU (4.5% and 11.2% grade 2) in a large cohort including 2143 patients [18]. Therefore, we believe that there is room to elevate the dose with meticulous caution for toxicity in high-risk prostate cancer.
For the delivery of SBRT, there are several radiation techniques used to deliver a large-fraction dose to the prostate [27][28][29][30]. RT modality, as provided by the robot-assisted technique Cyber Knife ® (CK), which can deliver such radiation within a high-fraction dose, is currently witnessing increased usage in the treatment of prostate cancer with low to intermediate risk [27][28][29][30]. IMRT techniques, including rotational approaches as helical tomotherapy and volumetric modulated arc therapy (VMAT), can also deliver a high daily fraction with high conformity and reduce the dose to the surrounding healthy tissue. Chen et al. reported that, based on physical dosimetry and radiobiologic considerations, helical tomotherapy may have advantages over CK, specifically in rectal sparing, which could translate into the clinical benefit of decreased late toxicities [30]. The series of studies showing good dosimetric quality for several SBRT techniques for the treatment of localized prostate cancer was demonstrated [27][28][29][30].
This study has several limitations. First, its retrospective nature, limited follow-up time (especially for the UHF group), and the small sample size may limit its application. We admitted our efficacy data for UHF were not conclusive but suggestive. Second, other predisposing factors should be discussed, including prescribed dose, meticulous dosimetric factors (V46Gy, etc.) [20], and non-dosimetric factors (prostate and irradiated volume, preexisting symptoms or surgery (Transurethral resection of the prostate, etc.), anticoagulant usage, daily versus every other day irradiation, etc.) [31]. Third, although using a free database is beneficial, retrospective databases may not record toxicity and tumor control outcomes and may rather be ambiguous according to the schedule of heterogeneous follow-up periods.

Conclusions
UHF showed equivalent outcomes to DeRT, although not conclusive but suggestive due to the short follow-up period of the UHF arm. As L-UHF showed lower toxicity than H-UHF, L-UHF using EQD2 ≤ 100 Gy 1.5 is a feasible UHF schedule with a good balance between toxicity and efficacy.
Supplementary Materials: The following supporting information can be downloaded at: https: //www.mdpi.com/article/10.3390/cancers14010195/s1. Table S1. Patients' characteristics between ultrahypofrationated and conventional to medium hypofractionated radiotherapy after propensity score matching. Table S2. Patient characteristics between H-UHF and L-UHF groups. Data Availability Statement: The data of UHF and part of EBRT for this manuscript can be obtained from the public database [6] and another part of EBRT can be obtained from the author upon reasonable request.